Oligogenic Disease

  • Jon F. Robinson
  • Nicholas Katsanis

Abstract

One of the primary goals of human and medical genetics is to assign predictive value to the genotype — that is to say, to use genetic information to assist in the diagnosis and management of disease. Recent work, originating primarily from disorders thought to be traditionally inherited in a Mendelian fashion, have blurred the boundaries between allele causality in monogenic and complex disease. Studies on genetic variation in disease are now revealing that essentially no disorder is transmitted solely in a Mendelian fashion; rather there are always multiple genetic and environmental factors that cause or modulate a disease phenotype. The focus of this chapter, oligogenic disorders, a term describing diseases caused by, or modulated by, a few genes, can provide a conceptual bridge between diseases classically considered monogenic and the poorly understood polygenic or complex disorders.

The inheritance of alleles generally follows Mendelian laws of segregation and independent assortment. However, this axiom does not necessarily hold true when the segregation of disease traits is considered. Mendelian inheritance is founded on the notion that a trait (not exclusively a disease phenotype) is transmitted through a single locus; however, even in the most classic monogenic disorders the 1:1 or 3:1 Mendelian ratio of dominant to recessive phenotypes, respectively, cannot explain the breadth of phenotypic variation found in a clinical setting. Although environment also plays a part, new research is showing that a large amount of the pheno-typic variation in “Mendelian” disorders is due to genetic interaction of several genes (Nat Rev Genet 3:779–789, 2002). In that context, most, if not all, disorders should be considered multifactorial; and the main reason they are Mendelized is that the majority of the phenotype can be attributed to variation/mutations at a single locus.

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References

  1. 1.
    Adato A, Kalinski H, Weil D, Chaib H, Korostishevsky M, Bonne-Tamir B (1999) Possible interaction between USH1B and USH3 gene products as implied by apparent digenic deafness inheritance. Am J Hum Genet 65:261–265CrossRefPubMedGoogle Scholar
  2. 2.
    Arai K, Zachman K, Shibasaki T, Chrousos GP (1999) Polymorphisms of amiloride-sensitive sodium channel sub-units in five sporadic cases of pseudohypoaldosteronism: do they have pathologic potential? J Clin Endocrinol Metab 84:2434–2437CrossRefPubMedGoogle Scholar
  3. 3.
    Arighi E, Borrello MG, Sariola H (2005) RET tyrosine kinase signaling in development and cancer. Cytokine Growth Factor Rev 16:441–467CrossRefPubMedGoogle Scholar
  4. 4.
    Attie T, Pelet A, Edery P, Eng C, Mulligan LM, Amiel J, Boutrand L, Beldjord C, Nihoul-Fekete C, Munnich A (1995) Diversity of RET proto-oncogene mutations in familial and sporadic Hirschsprung disease. Hum Mol Genet 4:1381–1386CrossRefPubMedGoogle Scholar
  5. 5.
    Badano JL, Katsanis N (2002) Beyond mendel: an evolving view of human genetic disease transmission. Nat Rev Genet 3:779–789CrossRefPubMedGoogle Scholar
  6. 6.
    Badano JL, Leitch CC, Ansley SJ, May-Simera H, Lawson S, Lewis RA, Beales PL, Dietz HC, Fisher S, Katsanis N (2006) Dissection of epistasis in oligogenic Bardet—Biedl syndrome. Nature 439:326–330CrossRefPubMedGoogle Scholar
  7. 7.
    Badano JL, Mitsuma N, Beales PL, Katsanis N (2006) The ciliopathies: an emerging class of human genetic disorders. Annu Rev Genomics Hum Genet 7:125–148CrossRefPubMedGoogle Scholar
  8. 8.
    Balciuniene J, Dahl N, Borg E, Samuelsson E, Koisti MJ, Pettersson U, Jazin EE (1998) Evidence for digenic inheritance of nonsyndromic hereditary hearing loss in a swedish family. Am J Hum Genet 63:786–793CrossRefPubMedGoogle Scholar
  9. 9.
    Bapat B, Odze R, Mitri A, Berk T, Ward M, Gallinger S (1993) Identification of somatic APC gene mutations in periampullary adenomas in a patient with familial adenoma-tous polyposis (FAP). Hum Mol Genet 2:1957–1959CrossRefPubMedGoogle Scholar
  10. 10.
    Beales PL, Katsanis N, Lewis RA, Ansley SJ, Elcioglu N, Raza J, Woods MO, Green JS, Parfrey PS, Davidson WS, Lupski JR (2001) Genetic and mutational analyses of a large multiethnic Bardet—Biedl cohort reveal a minor involvement of BBS6 and delineate the critical intervals of other loci. Am J Hum Genet 68:606–616CrossRefPubMedGoogle Scholar
  11. 11.
    Beales PL, Elcioglu N, Woolf AS, Parker D, Flinter FA (1999) New criteria for improved diagnosis of Bardet—Biedl syndrome: results of a population survey. J Med Genet 36:437–446PubMedGoogle Scholar
  12. 12.
    Beales PL, Badano JL, Ross AJ, Ansley SJ, Hoskins BE, Kirsten B, Mein CA, Froguel P, Scambler PJ, Lewis RA, Lupski JR, Katsanis N (2003) Genetic interaction of BBS1 mutations with alleles at other BBS loci can result in non-Mendelian Bardet—Biedl syndrome. Am J Hum Genet 72:1187–1199CrossRefPubMedGoogle Scholar
  13. 13.
    Benailly HK, Lapierre JM, Laudier B, Amiel J, Attie T, De Blois MC, Vekemans M, Romana SP (2003) PMX2B, a new candidate gene for Hirschsprung's disease. Clin Genet 64:204–209CrossRefPubMedGoogle Scholar
  14. 14.
    Berthet M, Denjoy I, Donger C, Demay L, Hammoude H, Klug D, Schulze-Bahr E, Richard P, Funke H, Schwartz K, Coumel P, Hainque B, Guicheney P (1999) C-terminal HERG mutations: the role of hypokalemia and a KCNQ1-associated mutation in cardiac event occurrence. Circulation 99:1464–1470PubMedGoogle Scholar
  15. 15.
    Biason-Lauber A, Suter SL, Shackleton CH, Zachmann M (2000) Apparent cortisone reductase deficiency: a rare cause of hyperandrogenemia and hypercortisolism. Horm Res 53:260–266CrossRefPubMedGoogle Scholar
  16. 16.
    Blau N, Thony B, Heizmann CW, Dhondt JA (1993) Tetra-hydrobiopterin deficiency: from phenotype to genotype. Pteridines 4:1–10Google Scholar
  17. 17.
    Bolk S, Pelet A, Hofstra RM, Angrist M, Salomon R, Croaker D, Buys CH, Lyonnet S, Chakravarti A (2000) A human model for multigenic inheritance: phenotypic expression in Hirschsprung disease requires both the RET gene and a new 9q31 locus. Proc Natl Acad Sci USA 97:268–273CrossRefPubMedGoogle Scholar
  18. 18.
    Brose K, Bland KS, Wang KH, Arnott D, Henzel W, Goodman CS, Tessier-Lavigne M, Kidd T (1999) Slit proteins bind robo receptors and have an evolutionarily conserved role in repulsive axon guidance. Cell 96:795–806CrossRefPubMedGoogle Scholar
  19. 19.
    Bruning JC, Winnay J, Bonner-Weir S, Taylor SI, Accili D, Kahn CR (1997) Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles. Cell 88:561–572CrossRefPubMedGoogle Scholar
  20. 20.
    Cormier RT, Hong KH, Halberg RB, Hawkins TL, Richardson P, Mulherkar R, Dove WF, Lander ES (1997) Secretory phospholipase Pla2g2a confers resistance to intestinal tumorigenesis. Nat Genet 17:88–91CrossRefPubMedGoogle Scholar
  21. 21.
    Cutting GR (2005) Modifier genetics: cystic fibrosis. Annu Rev Genomics Hum Genet 6:237–260CrossRefPubMedGoogle Scholar
  22. 22.
    Dachsel JC, Mata IF, Ross OA, Taylor JP, Lincoln SJ, Hinkle KM, Huerta C, Ribacoba R, Blazquez M, Alvarez V, Farrer MJ (2006) Digenic Parkinsonism: investigation of the syner-gistic effects of PRKN and LRRK2. Neurosci Lett 410: 80–84CrossRefPubMedGoogle Scholar
  23. 23.
    Dahia PL, Hao K, Rogus J, Colin C, Pujana MA, Ross K, Magoffin D, Aronin N, Cascon A, Hayashida C Y, Li C, Toledo SP, Stiles CD, Familial heochromocytoma Consortium (2005) Novel pheochromocytoma susceptibility loci identi-fied by integrative genomics. Cancer Res 65:9651–9658CrossRefPubMedGoogle Scholar
  24. 24.
    Davis JS, Hassanzadeh S, Winitsky S, Lin H, Satorius C, Vemuri R, Aletras AH, Wen H, Epstein ND (2001) The overall pattern of cardiac contraction depends on a spatial gradient of myosin regulatory light chain phosphorylation. Cell 107:631–641CrossRefPubMedGoogle Scholar
  25. 25.
    del Castillo FJ, Rodriguez-Ballesteros M, Alvarez A, Hutchin T, Leonardi E, de Oliveira CA, Azaiez H et al (2005) A novel deletion involving the connexin-30 gene, del(GJB6–d13s1854), found in trans with mutations in the GJB2 gene (connexin-26) in subjects with DFNB1 non-syndromic hearing impairment. J Med Genet 42:588–594CrossRefPubMedGoogle Scholar
  26. 26.
    Dietrich WF, Lander ES, Smith JS, Moser AR, Gould KA, Luongo C, Borenstein N, Dove W (1993) Genetic identification of mom-1, a major modifier locus affecting min-induced intestinal neoplasia in the mouse. Cell 75:631–639CrossRefPubMedGoogle Scholar
  27. 27.
    Dode C, Teixeira L, Levilliers J, Fouveaut C, Bouchard P, Kottler ML, Lespinasse J, Lienhardt-Roussie A, Mathieu M, Moerman A, Morgan G, Murat A, Toublanc JE, Wolczynski S, Delpech M, Petit C, Young J, Hardelin JP (2006) Kallmann syndrome: mutations in the genes encoding pro-kineticin-2 and prokineticin receptor-2. PLoS Genet 2:e175CrossRefPubMedGoogle Scholar
  28. 28.
    Doray B, Salomon R, Amiel J, Pelet A, Touraine R, Billaud M, Attie T, Bachy B, Munnich A, Lyonnet S (1998) Mutation of the RET ligand, neurturin, supports multigenic inheritance in hirschsprung disease. Hum Mol Genet 7:1449–1452CrossRefPubMedGoogle Scholar
  29. 29.
    Draper N, Walker EA, Bujalska IJ, Tomlinson JW, Chalder SM, Arlt W, Lavery GG, Bedendo O, Ray DW, Laing I, Malunowicz E, White PC, Hewison M, Mason PJ, Connell JM, Shackleton CH, Stewart PM (2003) Mutations in the genes encoding 11beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency. Nat Genet 34:434–439CrossRefPubMedGoogle Scholar
  30. 30.
    Edery P, Lyonnet S, Mulligan LM, Pelet A, Dow E, Abel L, Holder S, Nihoul-Fekete C, Ponder BA, Munnich A (1994) Mutations of the RET proto-oncogene in Hirschsprung's disease. Nature 367:378–380CrossRefPubMedGoogle Scholar
  31. 31.
    Emison ES, McCallion AS, Kashuk CS, Bush RT, Grice E, Lin S, Portnoy ME, Cutler DJ, Green ED, Chakravarti A (2005) A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk. Nature 434: 857–863CrossRefPubMedGoogle Scholar
  32. 32.
    Ficarella R, Di Leva F, Bortolozzi M, Ortolano S, Donaudy F, Petrillo M, Melchionda S, Lelli A, Domi T, Fedrizzi L, Lim D, Shull GE, Gasparini P, Brini M, Mammano F, Carafoli E (2007) A functional study of plasma-membrane calcium-pump isoform 2 mutants causing digenic deafness. Proc Natl Acad Sci USA 104:1516–1521CrossRefPubMedGoogle Scholar
  33. 33.
    Gabriel SB, Salomon R, Pelet A, Angrist M, Amiel J, Fornage M, Attie-Bitach T, Olson JM, Hofstra R, Buys C, Steffann J, Munnich A, Lyonnet S, Chakravarti A (2002) Segregation at three loci explains familial and population risk in Hirschsprung disease. Nat Genet 31:89–93PubMedGoogle Scholar
  34. 34.
    Gandrille S, Greengard JS, Alhenc-Gelas M, Juhan-Vague I, Abgrall JF, Jude B, Griffin JH, Aiach M (1995) Incidence of activated protein C resistance caused by the ARG 506 GLN mutation in factor V in 113 unrelated symptomatic protein C-deficient patients. The French Network on the behalf of INSERM. Blood 86:219–224PubMedGoogle Scholar
  35. 35.
    Gibson G, Dworkin I (2004) Uncovering cryptic genetic variation. Nat Rev Genet 5:681–690CrossRefPubMedGoogle Scholar
  36. 36.
    Glorioso N, Filigheddu F, Troffa C, Soro A, Parpaglia PP, Tsikoudakis A, Myers RH, Herrera VL, Ruiz-Opazo N (2001) Interaction of alpha(1)-na, K-ATPase and na, K, 2Cl-cotransporter genes in human essential hypertension. Hypertension 38:204–209PubMedGoogle Scholar
  37. 37.
    Goldberg AF, Molday RS (1996) Subunit composition of the peripherin/rds-rom-1 disk rim complex from rod photo-receptors: hydrodynamic evidence for a tetrameric quaternary structure. Biochemistry 35:6144–6149CrossRefPubMedGoogle Scholar
  38. 38.
    Gouya L, Puy H, Lamoril J, Da Silva V, Grandchamp B, Nordmann Y, Deybach JC (1999) Inheritance in erythropoi-etic protoporphyria: a common wild-type ferrochelatase allelic variant with low expression accounts for clinical manifestation. Blood 93:2105–2110PubMedGoogle Scholar
  39. 39.
    Grieco M, Santoro M, Berlingieri MT, Melillo RM, Donghi R, Bongarzone I, Pierotti MA, Della Porta G, Fusco A, Vecchio G (1990) PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell 60:557–563CrossRefPubMedGoogle Scholar
  40. 40.
    Griffiths AJF, Miller JH, Suzuki DT, Lewontin RC, Gelbart WM (1999) Introduction to genetic analysis. WH Freeman and Company, New YorkGoogle Scholar
  41. 41.
    Hansford JR, Mulligan LM (2000) Multiple endocrine neo-plasia type 2 and RET: from neoplasia to neurogenesis. J Med Genet 37:817–827CrossRefPubMedGoogle Scholar
  42. 42.
    Hanson EH, Imperatore G, Burke W (2001) HFE gene and hereditary hemochromatosis: a HuGE review. Human genome epidemiology. Am J Epidemiol 154:193–206CrossRefPubMedGoogle Scholar
  43. 43.
    Haravuori H, Siitonen HA, Mahjneh I, Hackman P, Lahti L, Somer H, Peltonen L, Kestila M, Udd B (2004) Linkage to two separate loci in a family with a novel distal myopathy phenotype (MPD3). Neuromuscul Disord 14:183–187CrossRefPubMedGoogle Scholar
  44. 44.
    Helwig U, Imai K, Schmahl W, Thomas BE, Varnum DS, Nadeau JH, Balling R (1995) Interaction between undulated and patch leads to an extreme form of spina bifida in double-mutant mice. Nat Genet 11:60–63CrossRefPubMedGoogle Scholar
  45. 45.
    Ito M, Yamakawa K, Sugawara T, Hirose S, Fukuma G, Kaneko S (2006) Phenotypes and genotypes in epilepsy with febrile seizures plus. Epilepsy Res 70(Suppl 1): S199–S205CrossRefPubMedGoogle Scholar
  46. 46.
    Iwashita T, Kruger GM, Pardal R, Kiel MJ, Morrison SJ (2003) Hirschsprung disease is linked to defects in neural crest stem cell function. Science 301:972–976CrossRefPubMedGoogle Scholar
  47. 47.
    Jacolot S, Le Gac G, Scotet V, Quere I, Mura C, Ferec C (2004) HAMP as a modifier gene that increases the pheno-typic expression of the HFE pC282Y homozygous genotype. Blood 103:2835–2840CrossRefPubMedGoogle Scholar
  48. 48.
    Jervis GA (1953) Phenylpyruvic oligophrenia deficiency of phenylalanine-oxidizing system. Proc Soc Exp Biol Med 82:514–515PubMedGoogle Scholar
  49. 49.
    Joosten PH, van Zoelen EJ, Murre C (2005) Pax1/E2a double-mutant mice develop non-lethal neural tube defects that resemble human malformations. Transgenic Res 14:983–987CrossRefPubMedGoogle Scholar
  50. 50.
    Katsanis N (2004) The oligogenic properties of Bardet— Biedl syndrome. Hum Mol Genet 13(Spec No 1):R65–R71CrossRefPubMedGoogle Scholar
  51. 51.
    Katsanis N, Ansley SJ, Badano JL, Eichers ER, Lewis RA, Hoskins BE, Scambler PJ, Davidson WS, Beales PL, Lupski JR (2001) Triallelic inheritance in Bardet—Biedl syndrome, a Mendelian recessive disorder. Science 293:2256–2259CrossRefPubMedGoogle Scholar
  52. 52.
    Kerem B, Rommens JM, Buchanan JA, Markiewicz D, Cox TK, Chakravarti A, Buchwald M, Tsui LC (1989) Identification of the cystic fibrosis gene: genetic analysis. Science 245:1073–1080CrossRefPubMedGoogle Scholar
  53. 53.
    Kidd T, Bland KS, Goodman CS (1999) Slit is the midline repellent for the robo receptor in Drosophila. Cell 96: 785–794CrossRefPubMedGoogle Scholar
  54. 54.
    Le Gac G, Ferec C (2005) The molecular genetics of haemo-chromatosis. Eur J Hum Genet 13:1172–1185CrossRefPubMedGoogle Scholar
  55. 55.
    Le Gac G, Scotet V, Ka C, Gourlaouen I, Bryckaert L, Jacolot S, Mura C, Ferec C (2004) The recently identified type 2A juvenile haemochromatosis gene (HJV), a second candidate modifier of the C282Y homozygous phenotype. Hum Mol Genet 13:1913–1918CrossRefPubMedGoogle Scholar
  56. 56.
    Leppert M, Burt R, Hughes JP, Samowitz W, Nakamura Y, Woodward S, Gardner E, Lalouel JM, White R (1990) Genetic analysis of an inherited predisposition to colon cancer in a family with a variable number of adenomatous polyps. N Engl J Med 322:904–908PubMedCrossRefGoogle Scholar
  57. 57.
    Li JB, Gerdes JM, Haycraft CJ, Fan Y, Teslovich TM, May-Simera H, Li H, Blacque OE, Li L, Leitch CC, Lewis RA, Green JS, Parfrey PS, Leroux MR, Davidson WS, Beales PL, Guay-Woodford LM, Yoder BK, Stormo GD, Katsanis N, Dutcher SK (2004) Comparative genomics identifies a flagellar and basal body proteome that includes the BBS5 human disease gene. Cell 117:541–552CrossRefPubMedGoogle Scholar
  58. 58.
    Loewen CJ, Moritz OL, Molday RS (2001) Molecular characterization of peripherin-2 and rom-1 mutants responsible for digenic retinitis pigmentosa. J Biol Chem 276: 22388–22396CrossRefPubMedGoogle Scholar
  59. 59.
    MacPhee M, Chepenik KP, Liddell RA, Nelson KK, Siracusa LD, Buchberg AM (1995) The secretory phospho-lipase A2 gene is a candidate for the Mom1 locus, a major modifier of ApcMin-induced intestinal neoplasia. Cell 81:957–966CrossRefPubMedGoogle Scholar
  60. 60.
    McCright B, Lozier J, Gridley T (2002) A mouse model of alagille syndrome: Notch2 as a genetic modifier of Jag1 haploinsufficiency. Development 129:1075–1082PubMedGoogle Scholar
  61. 61.
    Mendez M, Sorkin L, Rossetti MV, Astrin KH, Del C Batlle AM, Parera VE, Aizencang G, Desnick RJ (1998) Familial porphyria cutanea tarda: characterization of seven novel uroporphyrinogen decarboxylase mutations and frequency of common hemochromatosis alleles. Am J Hum Genet 63:1363–1375CrossRefPubMedGoogle Scholar
  62. 62.
    Merryweather-Clarke AT, Cadet E, Bomford A, Capron D, Viprakasit V, Miller A, McHugh PJ, Chapman RW, Pointon JJ, Wimhurst VL, Livesey KJ, Tanphaichitr V, Rochette J, Robson KJ (2003) Digenic inheritance of mutations in HAMP and HFE results in different types of haemochroma-tosis. Hum Mol Genet 12:2241–2247CrossRefPubMedGoogle Scholar
  63. 63.
    Merryweather-Clarke AT, Pointon JJ, Jouanolle AM, Rochette J, Robson KJ (2000) Geography of HFE C282Y and H63D mutations. Genet Test 4:183–198CrossRefPubMedGoogle Scholar
  64. 64.
    Millat G, Chevalier P, Restier-Miron L, Da Costa A, Bouvagnet P, Kugener B, Fayol L, Gonzalez Armengod C, Oddou B, Chanavat V, Froidefond E, Perraudin R, Rousson R, Rodriguez-Lafrasse C (2006) Spectrum of pathogenic mutations and associated polymorphisms in a cohort of 44 unrelated patients with long QT syndrome. Clin Genet 70:214–227CrossRefPubMedGoogle Scholar
  65. 65.
    Moron FJ, Mendoza N, Vazquez F, Molero E, Quereda F, Salinas A, Fontes J, Martinez-Astorquiza T, Sanchez-Borrego R, Ruiz A (2006) Multilocus analysis of estrogen-related genes in Spanish postmenopausal women suggests an interactive role of ESR1, ESR2 and NRIP1 genes in the pathogenesis of osteoporosis. Bone 39:213–221CrossRefPubMedGoogle Scholar
  66. 66.
    Moser AR, Dove WF, Roth KA, Gordon JI (1992) The min (multiple intestinal neoplasia) mutation: its effect on gut epithelial cell differentiation and interaction with a modifier system. J Cell Biol 116:1517–1526CrossRefPubMedGoogle Scholar
  67. 67.
    Muntoni F, Bonne G, Goldfarb LG, Mercuri E, Piercy RJ, Burke M, Yaou RB, Richard P, Recan D, Shatunov A, Sewry CA, Brown SC (2006) Disease severity in dominant emery dreifuss is increased by mutations in both emerin and desmin proteins. Brain 129:1260–1268CrossRefPubMedGoogle Scholar
  68. 68.
    Mykytyn K, Nishimura DY, Searby CC, Shastri M, Yen HJ, Beck JS, Braun T, Streb LM, Cornier AS, Cox GF, Fulton AB, Carmi R, Luleci G, Chandrasekharappa SC, Collins FS, Jacobson SG, Heckenlively JR, Weleber RG, Stone EM, Sheffield VC (2002) Identification of the gene (BBS1) most commonly involved in Bardet—Biedl syndrome, a complex human obesity syndrome. Nat Genet 31:435–438PubMedGoogle Scholar
  69. 69.
    Nanni L, Ming JE, Bocian M, Steinhaus K, Bianchi DW, Die-Smulders C, Giannotti A, Imaizumi K, Jones KL, Campo MD, Martin RA, Meinecke P, Pierpont ME, Robin NH, Young ID, Roessler E, Muenke M (1999) The mutational spectrum of the sonic hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly. Hum Mol Genet 8:2479–2488CrossRefPubMedGoogle Scholar
  70. 70.
    Naveed M, Nath SK, Gaines M, Al-Ali MT, Al-Khaja N, Hutchings D, Golla J, Deutsch S, Bottani A, Antonarakis SE, Ratnamala U, Radhakrishna U (2007) Genomewide linkage scan for split-hand/foot malformation with long-bone deficiency in a large arab family identifies two novel susceptibility loci on chromosomes 1q42.2-q43 and 6q14.1. Am J Hum Genet 80:105–111CrossRefPubMedGoogle Scholar
  71. 71.
    Pitteloud N, Quinton R, Pearce S, Raivio T, Acierno J, Dwyer A, Plummer L, Hughes V, Seminara S, Cheng YZ, Li WP, Maccoll G, Eliseenkova AV, Olsen SK, Ibrahimi OA, Hayes FJ, Boepple P, Hall JE, Bouloux P, Mohammadi M, Crowley W (2007) Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism. J Clin Invest 117:457–463CrossRefPubMedGoogle Scholar
  72. 72.
    Qin M, Hayashi H, Oshima K, Tahira T, Hayashi K, Kondo H (2005) Complexity of the genotype-phenotype correlation in familial exudative vitreoretinopathy with mutations in the LRP5 and/or FZD4 genes. Hum Mutat 26:104–112CrossRefPubMedGoogle Scholar
  73. 73.
    Reardon W, Smith A, Honour JW, Hindmarsh P, Das D, Rumsby G, Nelson I, Malcolm S, Ades L, Sillence D, Kumar D, DeLozier-Blanchet C, McKee S, Kelly T, McKeehan WL, Baraitser M, Winter RM (2000) Evidence for digenic inheritance in some cases of Antley–Bixler syndrome? J Med Genet 37:26–32CrossRefPubMedGoogle Scholar
  74. 74.
    Renieri A, Meloni I, Longo I, Ariani F, Mari F, Pescucci C, Cambi F (2003) Rett syndrome: the complex nature of a monogenic disease. J Mol Med 81:346–354PubMedGoogle Scholar
  75. 75.
    Roetto A, Camaschella C (2005) New insights into iron homeostasis through the study of non-HFE hereditary haemo-chromatosis. Best Pract Res Clin Haematol 18:235–250CrossRefPubMedGoogle Scholar
  76. 76.
    Savage DB, Agostini M, Barroso I, Gurnell M, Luan J, Meirhaeghe A, Harding AH, Ihrke G, Rajanayagam O, Soos MA, George S, Berger D, Thomas EL, Bell JD, Meeran K, Ross RJ, Vidal-Puig A, Wareham NJ, O'Rahilly S, Chatterjee VK, Schafer AJ (2002) Digenic inheritance of severe insulin resistance in a human pedigree. Nat Genet 31:379–384PubMedGoogle Scholar
  77. 77.
    Sayer JA, Otto EA, O'Toole JF, Nurnberg G, Kennedy MA, Becker C, Hennies HC et al (2006) The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. Nat Genet 38: 674–681CrossRefPubMedGoogle Scholar
  78. 78.
    Sebat J, Lakshmi B, Troge J, Alexander J, Young J, Lundin P, Maner S, Massa H, Walker M, Chi M, Navin N, Lucito R, Healy J, Hicks J, Ye K, Reiner A, Gilliam TC, Trask B, Patterson N, Zetterberg A, Wigler M (2004) Large-scale copy number polymorphism in the human genome. Science 305:525–528CrossRefPubMedGoogle Scholar
  79. 79.
    Silverman KA, Koratkar R, Siracusa LD, Buchberg AM (2002) Identification of the modifier of min 2 (Mom2) locus, a new mutation that influences apc-induced intestinal neo-plasia. Genome Res 12:88–97CrossRefPubMedGoogle Scholar
  80. 80.
    Snieder H, MacGregor AJ, Spector TD, NetLibrary I (2000) Advances in twin and sib-pair analysis. Greenwich Medical Media, London Distributed worldwide by Oxford University Press, OxfordGoogle Scholar
  81. 81.
    Spirio L, Otterud B, Stauffer D, Lynch H, Lynch P, Watson P, Lanspa S, Smyrk T, Cavalieri J, Howard L (1992) Linkage of a variant or attenuated form of adenomatous polyposis coli to the adenomatous polyposis coli (APC) locus. Am J Hum Genet 51:92–100PubMedGoogle Scholar
  82. 82.
    Spirio L, Olschwang S, Groden J, Robertson M, Samowitz W, Joslyn G, Gelbert L, Thliveris A, Carlson M, Otterud B (1993) Alleles of the APC gene: an attenuated form of familial polyposis. Cell 75:951–957CrossRefPubMedGoogle Scholar
  83. 83.
    Steingrimsson E, Tessarollo L, Pathak B, Hou L, Arnheiter H, Copeland NG, Jenkins NA (2002) Mitf and Tfe3, two members of the mitf-tfe family of bHLH-zip transcription factors, have important but functionally redundant roles in osteoclast development. Proc Natl Acad Sci USA 99:4477–4482CrossRefPubMedGoogle Scholar
  84. 84.
    Stoetzel C, Laurier V, Davis EE, Muller J, Rix S, Badano JL, Leitch CC et al (2006) BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus. Nat Genet 38:521–524CrossRefPubMedGoogle Scholar
  85. 85.
    Stoetzel C, Muller J, Laurier V, Davis EE, Zaghloul NA, Vicaire S, Jacquelin C, Plewniak F, Leitch CC, Sarda P, Hamel C, de Ravel TJ, Lewis RA, Friederich E, Thibault C, Danse JM, Verloes A, Bonneau D, Katsanis N, Poch O, Mandel JL, Dollfus H (2007) Identification of a novel BBS gene (BBS12) highlights the major role of a vertebrate-specific branch of chaperonin-related proteins in Bardet— Biedl syndrome. Am J Hum Genet 80:1–11CrossRefPubMedGoogle Scholar
  86. 86.
    Strachan T, Read AP (1999) Human molecular genetics 2. Garland Science, New YorkGoogle Scholar
  87. 87.
    Su LK, Kinzler KW, Vogelstein B, Preisinger AC, Moser AR, Luongo C, Gould KA, Dove WF (1992) Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 256:668–670CrossRefPubMedGoogle Scholar
  88. 88.
    Sundin OH, Jun AS, Broman KW, Liu SH, Sheehan SE, Vito EC, Stark WJ, Gottsch JD (2006) Linkage of late-onset fuchs corneal dystrophy to a novel locus at 13pTel-13q12.13. Invest Ophthalmol Vis Sci 47:140–145CrossRefPubMedGoogle Scholar
  89. 89.
    Tang B, Xiong H, Sun P, Zhang Y, Wang D, Hu Z, Zhu Z, Ma H, Pan Q, Xia JH, Xia K, Zhang Z (2006) Association of PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson's disease. Hum Mol Genet 15:1816–1825CrossRefPubMedGoogle Scholar
  90. 90.
    Tonooka N, Tomura H, Takahashi Y, Onigata K, Kikuchi N, Horikawa Y, Mori M, Takeda J (2002) High frequency of mutations in the HNF-1alpha gene in non-obese patients with diabetes of youth in Japanese and identification of a case of digenic inheritance. Diabetologia 45:1709–1711CrossRefPubMedGoogle Scholar
  91. 91.
    Touitou I, Perez C, Dumont B, Federici L, Jorgensen C (2006) Refractory auto-inflammatory syndrome associated with digenic transmission of low-penetrance tumour necrosis factor receptor-associated periodic syndrome and cry-opyrin-associated periodic syndrome mutations. Ann Rheum Dis 65:1530–1531CrossRefPubMedGoogle Scholar
  92. 92.
    Van Goethem G, Lofgren A, Dermaut B, Ceuterick C, Martin JJ, Van Broeckhoven C (2003) Digenic progressive external ophthalmoplegia in a sporadic patient: recessive mutations in POLG and C10orf2/Twinkle. Hum Mutat 22:175–176CrossRefPubMedGoogle Scholar
  93. 93.
    White PC, Speiser PW (2000) Congenital adrenal hyperpla-sia due to 21-hydroxylase deficiency. Endocr Rev 21:245–291CrossRefPubMedGoogle Scholar
  94. 94.
    Woo SL, Lidsky AS, Guttler F, Chandra T, Robson KJ (1983) Cloned human phenylalanine hydroxylase gene allows prenatal diagnosis and carrier detection of classical phenylketonuria. Nature 306:151–155CrossRefPubMedGoogle Scholar
  95. 95.
    Yook KJ, Proulx SR, Jorgensen EM (2001) Rules of nonal-lelic noncomplementation at the synapse in caenorhabditis elegans. Genetics 158:209–220PubMedGoogle Scholar
  96. 96.
    Zheng QY, Yan D, Ouyang XM, Du LL, Yu H, Chang B, Johnson KR, Liu XZ (2005) Digenic inheritance of deafness caused by mutations in genes encoding cadherin 23 and protocadherin 15 in mice and humans. Hum Mol Genet 14:103–111CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  • Jon F. Robinson
    • 1
  • Nicholas Katsanis
    • 2
  1. 1.McKusick-Nathans Institute of Genetic MedicineDepartment of Molecular Biology and Genetics Johns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Department of Cell BiologyDuke UniversityDurhamUSA

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